Transient Receptor Potential A1 (herein, “TRPA1”) is a non-selective cation channel related to pain sensation in humans. TRPA1 is found in sensory neurons and functions as a detector that helps link detection of noxious chemicals, tissue damage, and inflammation to pain. Activation of TRPA1 is believed to cause pain by inducing firing of nociceptive neurons and driving central sensitization in the spinal cord. TRPA1 stimulation can also increase firing of sensory neurons, leading to the release of pro-inflammatory neuropeptides such as NK-A, substance P and CGRP, which induce vasodilation and help recruit immune cells. A variety of endogenous reactive compounds produced during inflammation activate TRPA1, including 4-hydroxynonenal released during liposome peroxidation; cyclopentane prostaglandins synthesized by COX enzymes; hydrogen peroxide produced by oxidative stress. Activation of TRPA1 also sensitizes TRPA1 to cold. Furthermore, a gain-of-function mutation in TRPA1 causes familial episodic pain syndrome; patients suffering from this condition have episodic pain that may be triggered by cold. Thus, TRPA1 is considered to play a role in pain related to nerve damage, cold allodynia, and inflammatory pain.
Compounds that inhibit the TRPA1 ion channel can be useful, for example, in treating conditions ameliorated, eliminated, or prevented by inhibition of the TRPA1 ion channel. For example, pharmaceutical compositions that inhibit TRPA1 can be used to treat pain. Inhibition of TRPA1 (e.g., by genetic ablation and chemical antagonism) has been shown to result in reduced pain behavior in mice and rats. Knockout mice lacking functional TRPA1 have diminished nociceptive responses to TRPA1 activators, including AITC, formalin, acrolein, 4-hydroxynonenal, and, in addition, have greatly reduced thermal and mechanical hypersensitivity in response to the inflammatory mediator bradykinin (e.g., Kwan, K. Y. et al. Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006, 124, 1269-1282). In animal pain models, down regulation of TRPA1 expression by gene specific antisenses prevented and reversed cold hyperalgesia induced by inflammation and nerve injury (see, e.g., Obata, K. et al., J Clin Invest (2005) 115, 2393-2401; Jordt, S. E. et al., Nature (2004), 427, 260-265; Katsura, H. et al., Explor Neurol (2006), 200, 112-123). TRPA1 inhibitor compounds are effective in a variety of rodent pain models. TRPA1 inhibitors have been shown to reduce mechanical hypersensitivity and cold allodynia following inflammation induced by Complete Freund's Adjuvant without altering normal cold sensation in naïve animals and also to improve function in the rat mono-iodoacetate osteoarthritis model (see, e.g., Materazzi, S et al., Eur J Physiol (2012), 463(4):561-9; Wei H et al., Anesthesiology 2012, 117(1):137-48; Koivisto, A et al., Pharmacol Res (2012), 65(1):149-58). TRPA1 inhibitor compounds have demonstrated reduced pain behavior in rodents injected with AITC (mustard oil), formalin, cinnamaldehyde, acrolein, and other TRPA1 activators. TRPA1 inhibitor compounds have also demonstrated efficacy in rodent models for post operative pain, (see, e.g., Wei et al., Anesthesiology (2012), 117(1):137-48); chemotherapy induced peripheral neuropathy (see, e.g., Trevisan, et al., Cancer Res (2013) 73(10):3120-31), and painful diabetic neuropathy (see, e.g., Koivisto et al., Pharmacol Res (2011) 65:149-158).